Steroid and thyroid hormones—intracellular receptors

See also Steroid Hormone Synthesis, Steroid Hormones, Steroid Metabolism, Steroids, Cytochrome P-450, Steroid and Thyroid Hormones - Intracellular Receptors... 

Receptor-effector mechanisms include (1) enzymes with catalytic activities, (2) ion channels that gate the transmembrane flux of ions (ionotropic receptors), (3) G protein-coupled receptors that activate intracellular messengers (metabotropic receptors), and (4) cytosolic receptors that regulate gene transcription. Cytosolic receptors are a specific mechanism of many steroid and thyroid hormones. The ionotropic and metabotropic receptors are discussed in relevance to specific neurotransmitters in chapter 2. 

The steroid and thyroid hormones, 1,25-DHC, and retinoic acid cross the cell membrane and bind to intracellular receptors, forming complexes that activate or inactivate genes. 

Hydrophobic hormones such as the steroids and thyroid hormones diffuse across cellular membranes and bind to intracellular receptors. 

Metabolism and interactions of metabolic pathways are strongly influenced by hormones and hormonal balance. Therefore, it is worthwhile to examine the effects of hormones on metabolism as well as the potential mechanism of action of the hormones. The mechanism of three major hormones (i.e., insulin, glucagon, and epinephrine) discussed previously are examined as well as others, such as steroid hormones. Many hormones, including those discussed earlier, which cause acute effects on metabolism, do not enter the cell, but must have a transduction to cause intracellular effects, although the hormone itself is bound to a receptor on the membrane. Others, such as steroid and thyroid hormones, enter the cell and have effects in the nucleus. 

Hormones bind specifically to hormone receptors with high affinity. Binding of a hormone to its receptor initiates a hormonal response. There are two general types of receptors cell-surface receptors and intracellular receptors. While protein and peptide hormones generally interact with cell-surface receptors, steroid and thyroid hormones act on intracellular receptors. 

Steroid and thyroid hormones act via intracellular receptors. Receptors may be found in the cytoplasm or in the nucleus. Glucocorticoid, mineralocorticoid, and androgen receptors are located in the cytoplasm, while estrogen, progesterone, thyroid hormone, 1,25-dihydroxycholecalciferol, and retinoic acid receptors are found in the nucleus. 

Figure 6. Idealized scheme of the mechanism of action of steroid and thyroid hormones using an intracellular binding protein or receptor. DNA, deoxyribonucleic acid RNA, ribonucleic acid Hn-RNA, heterogeneous RNA mRNA, messenger RNA.

Hormonal actions on target neurons are classified in terms of cellular mechanisms of action. Hormones act either via cell-surface or intracellular receptors. Peptide hormones and amino-acid derivatives, such as epinephrine, act on cell-surface receptors that do such things as open ion-channels, cause rapid electrical responses and facilitate exocytosis of hormones or neurotransmitters. Alternatively, they activate second-messenger systems at the cell membrane, such as those involving cAMP, Ca2+/ calmodulin or phosphoinositides (see Chs 20 and 24), which leads to phosphorylation of proteins inside various parts of the target cell (Fig. 52-2A). Steroid hormones and thyroid hormone, on the other hand, act on intracellular receptors in cell nuclei to regulate gene expression and protein synthesis (Fig. 52-2B). Steroid hormones can also affect cell-surface events via receptors at or near the cell surface. 

Several biologic ligands are sufficiently lipid-soluble to cross the plasma membrane and act on intracellular receptors. One class of such ligands includes steroids (corticosteroids, mineralocorticoids, sex steroids, vitamin D), and thyroid hormone,... 

The receptors for all classes of steroid hormones, including the receptors for 1,25-dihydroxy vitamin D3, and thyroid hormones are intracellular proteins that are not very abundant, usually only 102-105 molecules per cell. 

It is assumed that some compounds of this group (AHTN and ATTN) may bind to the retinoid acid receptor (RAR) or retinoid X receptor (RXR) because their structure shows some similarity with synthetic RXR ligands [364,365]. The RAR and RXR belong to the steroid/thyroid hormone nuclear receptor super family. They play a central role in the regulation of many intracellular receptor pathways [366]. However, all these assumptions and predictions, especially the predicted high bioconcentration potential of the PMFs, have to be investigated experimentally. 

In this section, we discuss the second major group of extracellular signals, the small, llpid-soluble hormones— Including many different steroid hormones, retinoids, and thyroid hormones—that can diffuse through plasma and nuclear membranes and Interact directly with the transcription factors they control (Figure 11-40). As noted earlier, the intracellular receptors for most of these llpid-soluble hormones,... 

Lipophilic hormones that use intracellular gene-specific transcription factors include the steroid hormones, thyroid hormone, retinoic acid (active form of vitamin A), and vitamin D (Fig. 11.8). Because these compounds are water-insoluble, they are transported in the blood bound to serum albumin, which has a hydrophobic binding pocket, or to a more specific transport protein, such as steroid hormonebinding globulin (SHBG) and thyroid hormone-binding globulin (TBG). The intracellular receptors for these hormones are structurally similar and are referred to as the steroid hormone/thyroid hormone superfamily of receptors. 

Amine hormones include the thyroid hormones and the catecholamines. The thyroid hormones tend to be biologically similar to the steroid hormones. They are mainly insoluble in the blood and are transported predominantly (>99%) bound to proteins. As such, these hormones have longer half-lives (triiodothyronine, t3, = 24 h thyroxine, T4, = 7 days). Furthermore, thyroid hormones cross cell membranes to bind with intracellular receptors and may be administered orally (e.g., synthryoid). In contrast to steroid hormones, however, thyroid hormones have the unique property of being stored extra-cellularly in the thyroid gland as part of the thyroglobulin molecule. 

The signal is what starts everything off. Signals take a variety of forms, but for our purposes there are only two. The first type are signals that go into the cell, bind to internal receptors, and exert their effects. Steroid hormones, vitamin D, thyroid hormone, and retinoids are the only members of this class. All of the intracellular receptors ultimately activate the transcription of regulated genes. The common feature of signals that enter the cell is that they are all small lipophilic molecules that can cross the cell membrane. 

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